The difficulty of detecting lung cancer at an early stage, its aggressiveness, the lack of effective systemic therapy, and the rapid development of resistance to chemotherapeutics are responsible for its high mortality. There is an urgent need for novel therapeutic strategies for the efficient treatment of lung cancer and new ways to overcome drug resistance. New treatments designed to restore functions of defective genes and gene products in tumor suppressing and apoptotic pathways by gene transfer and to target specific and frequently occurring molecular alterations in key signaling pathways by "smart drugs," such as protein tyrosine kinase (PTK) inhibitors, are fundamentally changing cancer therapy and hold promise for lung cancer treatment. Our goal is to develop an integrated therapeutic strategy for malignant lung cancer and metastases by combining a systemic and tumor-selective molecular therapy using DOTAP:Cholesterol-DNA nanoparticles with the novel multifunctional tumor suppressor gene FUS1 driven by a chimeric hTERT-mini-CMV (hTMC) promoter to directly activate the apoptotic pathway, a chemotherapy strategy using small molecule PTK inhibitors to specifically target the oncogenic PTK-mediated signaling pathway, and an innovative, noninvasive molecular imaging technique using an hTMC-SSRT2A-FUS1 vector system with magnetic resonance imaging and gamma-camera imaging to monitor the expression and anticancer efficacy of the therapeutic gene. This goal will be achieved via these Specific Aims: 1) evaluating the therapeutic efficacy of systemic administration of hTMC-FUS1 nanoparticles in human lung cancer mouse models;2) evaluating the therapeutic efficacy of treatment with FUS1 nanoparticles and novel small molecule PTK inhibitors erlotinib and imatinib in vitro and in vivo to enhance efficacy and overcome drug resistance in lung cancer;3) analyzing the interactions of the Fus1 protein with its cellular targets in tumor suppressing, apoptotic, and PTK signaling pathways to reveal the molecular mechanisms of FUS1-mediated tumor suppression and identify potential therapeutic targets;and 4) developing noninvasive molecular imaging technologies in mice for monitoring gene expression and biodistribution using the hTMC-FUS1-SSRT2A dual reporter and therapeutic gene expression system by gamma-camera imaging and for evaluation of the systemic therapeutic efficacy of FUS1-nanoparticles by magnetic resonance imaging analysis.